Kugita et al., U.S. Pat. No. 3,562,257 (Feb. 9, 1971), describes benzothiazepine derivatives, which are useful as antidepressants, tranquilizers and coronary vasodilators. Among these, diltiazem, i.e., 3-(acetyloxy)-5-[2-(dimethylamino)ethyl]-2,3-dihydro-2-(4-methoxyphenyl)-1 ,5-benzothiazepin-4(5H)-one, is a well-known successful cardiac drug having calcium blocking activity. Vasodilating action is specific for the d-cis-isomer, (+)-cis-5-[2-dimethylamino)ethyl]-2,3-dihydro-3-hydroxy-2- (p-methoxyphenyl)-1,5-benzothiazepin-4(5H)-one acetate (ester). The hydrochloride is often administered as, e.g., Cardizem.RTM.. Other 1,5-benzothiazepine derivatives are useful hypotensive agents and/or coronary or cerebral vasodilators and are known to have desired or enhanced effects from a select optical isomer as well. For example, (+)-cis-5-[2-dimethylamino)ethyl]-2,3-dihydro-3-acetoxy-2-(4-methoxyphenyl )-8-chloro-benzothiazepin-4(5H)-one and its pharmaceutically acceptable salt(s), etc. fit this category. See e.g., Takeda et al., U.S. Pat. No. 4,567.175 (Jan. 28, 1986). Further useful benzothiazepines are known as well. See e.g., present U.S. Pat. class 540 subclass 491, etc.
As might be expected, various processes or methods for preparing such benzothiazepines are generally further known. In order to isolate the desired optically active isomer such methods may typically include at least one resolution step.
Nagao et al., U.S. Pat. No. 4,416,819 (Nov. 22, 1983), describes a process for preparing 1,5-benzothiazepine derivatives. In preparing a racemic 2-hydroxy-3-(lower alkoxyphenyl)-3-(2-aminophenylthio)propionic acid used in that process, a 3-(lower alkoxyphenyl)glycidic acid ester is condensed with a 2-aminothiophenol in order to produce a 2-hydroxy-3-(lower alkoxyphenyl)-3-(2-aminophenylthio)propionic acid ester, which is hydrolyzed in order to produce the corresponding propionic acid intended to be employed in the process. That process is one which would employ a subsequent optical resolution step in order to isolate the desired optically active isomer as well.
Shimada et al., Jpn Koliai Tokkyo Koho Disclosure No. 78973-1985 (May 4, 1985), purportedly describes a method of producing 1,5-benzothiazepine derivatives. A racemic 3-(4-lower alkyoxyphenyl)glycidic acid lower alkyl ester is condensed with 2-aminothiophenol under neat conditions.
Sandada et al., Jpn. Discl. No. 268663-1988 (Nov. 28, 1986), discloses a method of producing optically active 2-hydroxy-3,3-di-substitued-propionic acid. Therein, a (2R,3S)-2,3-epoxy-3-(4-lower-alkoxyphenyl)propionic acid (-)menthyl ester purportedly is allowed to react with 2-aminothiophenol to produce 2(S)-hydroxy-3(S)-(4-lower-alkyloxyphenyl)-3-(2-aminophenylthio)propionic acid (-)-menthyl ester, followed by hydrolysis, which hydrolyzed acid product may be used to prepare corresponding 1,5-benzothiazepine derivatives, e.g., diltiazem hydrochloride.
In another particular type of method, a step intends condensing a 3-(4-alkyloxyphenyl)glycidic acid ester with a 2-nitrothiophenol in order to prepare a 2-hydroxy-3-(4-alkyloxyphenyl)-3-(2-nitrophenylthio)propionic acid ester. The starting epoxy esters may be optically active. Such a condensing step generally requires a catalyst or reaction accelerator, and these types of methods require a further step of reducing the aromatic nitro group to an amino in order to obtain the desired benzothiazepines. See e.g., Inoue et al., U.S. Pat. No. 4,420,628 (Dec. 13, 1983); Sawai et al., Jpn. Kokai Tokkyo Kojo No. 60-13775 (Jan. 24, 1985); Sawai et al., Jpn. Kokai Tokkyo Kojo No. 60-13776 (Jan. 24, 1985).
Ingarashi et al., U.S. Pat. No. 4,552,695 (Nov 12, 1985), describes a process for production of diltiazem hydrochloride. Steps in that 10-step process include employing an optically active 3-(4-acyloxyphenyl)glycidic acid ester, which is converted to a chlorohydrin. The chlorohydrin is allowed to react with an ortho-nitrothiophenol to obtain a 2-hydroxy-3-(4-acyloxyphenyl)-3-(2-nitrophenylthio)propionic acid ester. Subsequent steps include protecting the 2-hydroxy group, reducing the aromatic 2-nitro group to the 2-amino, and cyclizing, alkylating, acetylating and so forth.
Manghishi et al., U.S. Pat. No. 4,533,748 (Aug. 6, 1985), describes a process for the optical resolution of dl-2-hydroxy-3-(4-methoxyphenyl)-3-(2-aminophenylthio)propionic acid. The resolved (+).sub.D -isomer is an intermediate in the production of diltiazem.